ROCIFLEX "I.V./ I.M."
(VIALS)
(Ceftriaxone Sodium: Long-acting, broad-spectrum third generation cephalosporin antibiotic for parenteral use)
 

PROPERTIES & EFFECTS:
Microbiology: the bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone exerts in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Ceftriaxone is highly stable to most -lactamases, both penicillinases and cephalosporinases, of gram-positive and gram-negative bacteria. Ceftriaxone is usually active against the following microorganisms in vitro and in clinical infections.
Gram-positive aerobes: Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus group A (Strep. pyogenes), Streptococcus group B (Strep. agalactiae), Streptococcus viridans, Streptococcus bovis.
Note: Methicillin-resistant staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. Most strains of Enterococci (e.g., Streptococcus faecalis) are resistant.
Gram-negative aerobes: Aeromonas spp., Alcaligenes spp., Branhamella catarrhalis, Citrobacter spp., Enterobacter spp., Escherichia coli, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp., Moraxella spp., Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Plesiomonas shigelloides, Proteus mirabilis, Proteus vulgaris, Providencia spp., Pseudomonas aeruginosa, Salmonella spp., (including S. typhi), Serratia spp. (including S. marcescens), Shigella spp., Vibrio spp. (including V.cholerae), Yersinia spp., (including Y.enterocolitica).
Note: Many strains of the above microorganisms that are multiply resistant to other antibiotics, e.g., penicillins, older cephalosporins and aminoglycosides, are susceptible to ceftriaxone.
Treponema pallidum is sensitive in vitro and in animal experiments. Clinical investigations indicate that primary and secondary syphilis respond well to ceftriaxone therapy.
Anaerobic organisms, Bacteroides spp. (including some strains of B. fragilis), Clostridium spp. (except C. difficile), Fusobacterium spp. (except F. mortiferum and F. varium), Peptococcus spp., Peptostreptococcus spp.
Note: Many strains of -lactamase-producing Bacteroides spp. (notably B. fragilis) are resistant.
 

Pharmacokinetics:
Ceftriaxone is characterized by an unusually long elimination half-life of approximately eight hours in healthy adults. The area under the plasma concentration time curves after I.V. and I.M. administration is identical. This means that the bioavailability of ceftriaxone administered by I.M. is 100%. On intravenous administration, ceftriaxone diffuses rapidly into the interstitial fluid, where bactericidal concentration against susceptible organisms are maintained for 24 hours.
Concentration after 1 gr. ROCIFLEX.
Elimination: The elimination half-life in healthy adults is about eight hours, in infants and new born and in adults over 75 years of age, the average elimination half-life is about twice as long.
In adults, 50-60% of ceftriaxone is excreted unchanged by the kidneys, while 40-50% is excreted unchanged in the bile. The intestinal flora transforms ceftriaxone into inactive metabolites. In neonates, renal elimination accounts for about 70% of the dose. In patients with renal impairment or hepatic dysfunction, the pharmacokinetics of ceftriaxone is only minimally altered and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is increased.
Protein binding: Ceftriaxone is reversibly bound to albumin, and the binding decreases with the increase in the concentration, e.g., from 95% binding at plasma concentrations of <100 mg/l to 85% binding at 300 mg/l. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.
Penetration into the cerebrospinal fluid: Ceftriaxone penetrates the inflamed meninges of infants and children; the average extent of diffusion in the cerebrospinal fluid in bacterial meningitis is 17% of the plasma concentration, i.e., approximately four times that in aseptic meningitis.
Ceftriaxone concentrations of >1.4 mg/l have been found in the CSF 24 hours after I.V. injection of ROCIFLEX in doses of 50 -100 mg/kg. In adult meningitis patients, administration of 50 mg/kg leads within 2-24 hours to CSF concentrations several times higher than the minimum inhibitory concentrations required for the most common causative organisms of meningitis.
 

INDICATIONS:
ROCIFLEX is prescribed in the following infections caused by pathogens sensitive to ceftriaxone.
Sepsis; meningitis; abdominal infections (peritonitis, infections of the biliary and gastrointestinal tracts); infections of the bones, joints, soft tissue, skin and wounds; infections in patients with impaired defense mechanisms; renal and urinary tract infections; upper and lower respiratory tract infections, particularly pneumonia, and ear, nose and throat infections; genital infections, including gonorrhea. Perioperative prophylaxis of infections.
 

STANDARD DOSAGE:
Adults and children over twelve years: The usual dosage is 1 – 2 gr. of ROCIFLEX administered once daily (every 24 hours). In severe cases or in infections caused by moderately sensitive organisms, the dosage may be raised to 4 gr. administered once daily.
Neonates; infants and children up to twelve years: The following dosage schedules are recommended for once daily administration:
Neonates (up to two weeks): A daily dose of 20 – 50 mg/kg bodyweight, not to exceed 50 mg/kg, on account of the infant's enzyme systems.
Infants and children (three weeks to twelve years): A daily dose of 20 – 80 mg/kg bodyweight.
For children with bodyweights of 50 kg or more: The usual adult dosage should be used.
Intravenous doses of 50 mg. or more per kg should be given by infusion over at least 30 minutes.
Duration of therapy: The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of ROCIFLEX should be continued for a minimum of 48 – 72 hours after the patient has become a febrile or evidence of bacterial eradication has been obtained.
Combination therapy: Synergy between ROCIFLEX and aminoglycosides has been demonstrated with many gram-negative bacilli under experimental conditions. Although enhanced activity of such combinations is not always predictable, it should be considered in severe, life-threatening infections due to microorganisms such as pseudomonas aeruginosa. Because of physical incompatibility the two drugs must be administered separately at the recommended dosages.
 

SPECIAL DOSAGE INSTRUCTIONS
Meningitis: In bacterial meningitis in infants and children, treatment begins with doses of 100 mg/kg (not to exceed 4 gr.) once daily. As soon as the causative organism has been identified and its sensitivity determined, the dosage can be reduced accordingly. The best results have been found with the following duration of therapy:
Neisseria meningitis 4 days Streptococcus pneumoniae 7 days
Haemophilus influenzae 6 days susceptible enterobacteria 10-14 days
Gonorrhea: For the treatment of gonorrhea, a single I.M. dose of 250 mg. ROCIFLEX is recommended.
Preoperative prophylaxis: to prevent postoperative infections in contaminated or potentially contaminated surgery, the recommended approach (depending on the risk of infection) is a single dose of 1-2 gr. ROCIFLEX administered 30-90 minutes prior to surgery.
Impaired renal and hepatic function: In patients with impaired renal function, there is no need to reduce the dosage of ROCIFLEX provided hepatic function is intact. Only in cases of preterminal renal failure (creatinine clearance < 10 ml/min) should the ROCIFLEX dosage not exceed 2 gr. Daily. In patients with liver damage, there is no need for the dosage to be reduced provided renal function is intact.
In cases of concomitant severe renal and hepatic dysfunction, the plasma concentrations of ceftriaxone should be determined at regular intervals.
In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.


DOSAGE & ADMINISTRATION
Reconstituted solutions retain their physical and chemical stability for 6 hours at room temperature (or 24 hours at 5C). As a general rule, however, the solutions should be used immediately after preparation. They range in color from pale yellow to amber, depending on the concentration and the length of storage. This characteristic of the active ingredient is of no significance for the efficacy or tolerance of the drug.
Intramuscular injection: for I.M. injection;
ROCIFLEX 0.25 gr. is dissolved in 1 ml, of 1% lidocaine solution,
ROCIFLEX 0.5 gr. is dissolved in 2 ml, of 1% lidocaine solution,
ROCIFLEX 1 gr. is dissolved in 3.5 ml, of 1% lidocaine solution,
to be administered by deep intragluteal injection.
It is recommended that no more of 1 gr. be injected on either side.
The lidocaine solution must never be administered intravenously.
Intravenous injection: for I.V. injection,
ROCIFLEX 0.25 gr. is dissolved in 3 ml, of sterile water for injection,
ROCIFLEX 0.5 gr. is dissolved in 5 ml, of sterile water for injection,
ROCIFLEX 1 gr. is dissolved in 10 ml, of sterile water for injection,
then administered by I.V. injection lasting two to four minutes.
Intravenous infusion: the infusion should last at least 30 minutes. For I.V. infusion, 2 gr. ROCIFLEX are dissolved in 40 ml of one of the following calcium-free infusion solutions: sodium chloride 0.9 %, sodium chloride 0.45 % + dextrose 2.5 %, dextrose 5 %, dextrose 10 %, levulose 5 %, dextran 6 % in dextrose, sterile water for injections, ROCIFLEX solutions, should not be mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, owing to possible incompatibility.
 

CONTRAINDICATIONS
ROCIFLEX is contraindicated in patients with known hypersensitivity to the cephalosporin class of antibiotics. In patients hypersensitive to penicillin, the possibility of allergic cross-reactions should be kept in mind.
ROCIFLEX should not be used in pregnancy (particularly in the first trimester) unless absolutely indicated.
Precautions: As with other cephalosporins, anaphylactic shock cannot be ruled out even if a thorough patient history is taken. Anaphylactic shock requires immediate countermeasures such as intravenous epinephrine followed by a glucocorticoid etc.....
In rare cases, shadows suggesting sludge have been detected by sonograms of the gallbladder. This condition was reversible on discontinuation or completion of ROCIFLEX therapy. Even if such findings are associated with pain, conservative, non-surgical management is recommended.
In-vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Caution should be exercised when considering ROCIFLEX for hyperbilirubinemic neonates, especially prematures.
During prolonged treatment the blood picture should be checked at regular intervals.
Pregnancy: ROCIFLEX should not be used in pregnancy particularly in the first trimester, unless absolutely indicated.
Undesirable effects: ROCIFLEX is generally well tolerated. During the use of ROCIFLEX, the following side effects, which were reversible either spontaneously or after withdrawal of the drug, have been observed.
Systemic side effects: Gastrointestinal complaints (about 2 % of cases): loose stools or diarrhea, nausea, vomiting, stomatitis and glossitis.
Hematological changes (about 2 %): eosinophilia, leukopenia, granulocytopenia, hemolytic anemia, and thrombocytopenia.
Skin reactions (about 1 %): exanthema, allergic dermatitis, pruritus, urticaria, edema, erythema multiforme.
Other, rare side effects: headache and dizziness, increase in liver enzymes, gallbladder sludge, oliguria, increase in serum creatinine, mycosis of the genital tract, shivering and anaphylactic or anaphylactoid reactions.
Pseudomembranous enterocolitis and coagulation disorders have been reported as very rare
side effects.
Local side effects: In rare cases, phlebitic reactions occurred after I.V. administration. This may be prevented by slow (two to four minutes) injection of the substance.
Intramuscular injection without lidocaine solution is painful and contraindicated.
 

DRUG INTERACTIONS
No impairment of renal function has so far been observed after concurrent administration of large doses of ROCIFLEX and potent diuretics (e.g., furosemide). There is no evidence that ROCIFLEX increases renal toxicity of aminoglycosides. No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of ROCIFLEX.
Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins. The elimination of ROCIFLEX is not altered by probenecid.
 

PACKAGES & COMPOSITION
Note: ROCIFLEX could be used by I.M. route only if dissolved in lidocain 1% solution.
Each vial contains sterile dry powder substance equivalent to:
ROCIFLEX 1 gr.: sterile Ceftriaxone sodium, equiv. to ceftriaxone 1 gr.
ROCIFLEX 0.5 gr.: sterile Ceftriaxone sodium, equiv. to ceftriaxone 0.5 gr.
ROCIFLEX 0.25 gr.: sterile Ceftriaxone sodium, equiv. to ceftriaxone 0.25 gr.
 

STORAGE:
Store at room temperature away of heat and light.